Non-muscle myosin IIB (Myh10) is required for epicardial function and coronary vessel formation during mammalian development.

The coronary vasculature is an essential vessel network providing the blood supply to the heart. Disruptions in coronary blood flow contribute to cardiac disease, a major cause of premature death worldwide. The generation of treatments for cardiovascular disease will be aided by a deeper understanding of the developmental processes that underpin coronary vessel formation. From an ENU mutagenesis screen, we have isolated a mouse mutant displaying embryonic hydrocephalus and cardiac defects (EHC). Positional cloning and candidate gene analysis revealed that the EHC phenotype results from a point mutation in a splice donor site of the Myh10 gene, which encodes NMHC IIB. Complementation testing confirmed that the Myh10 mutation causes the EHC phenotype. Characterisation of the EHC cardiac defects revealed abnormalities in myocardial development, consistent with observations from previously generated NMHC IIB null mouse lines. Analysis of the EHC mutant hearts also identified defects in the formation of the coronary vasculature. We attribute the coronary vessel abnormalities to defective epicardial cell function, as the EHC epicardium displays an abnormal cell morphology, reduced capacity to undergo epithelial-mesenchymal transition (EMT), and impaired migration of epicardial-derived cells (EPDCs) into the myocardium. Our studies on the EHC mutant demonstrate a requirement for NMHC IIB in epicardial function and coronary vessel formation, highlighting the importance of this protein in cardiac development and ultimately, embryonic survival.

Tackling the challenge of the impact of continuing education: An evidence synthesis charting a global, cross-professional shift away from counting hours.

INTRODUCTION: Health professionals worldwide are required to maintain their knowledge and skills through continuing education. However, there is limited evidence that the accumulation of hours of educational activity enhances practice. The aim of this study was to review evidence of the impact of continuing professional development (CPD), best educational practice and new models of CPD requirements. METHODS: We conducted a rapid evidence synthesis, reviewing literature and websites on continuing education for healthcare and non-healthcare professionals. RESULTS: We extracted data from 184 publications. Evidence of changed practice and improved patient care is uncommon in studies of CPD. What evidence there is suggests that activities are more likely to have impact if a combination of methods is used and if they are aligned with learning needs. Impact is also affected by the learner and their work environment. In terms of CPD requirements, we identified three models: input-based; outcomes-based and mixed models. We found a clear shift from quantitative, time-serving, input-models to outcomes-focused models which emphasise the identification of learning needs, selection of educational activity relevant to practice and reflection on practice improvement. Across a range of professions, recently updated CPD regulations no longer require registrants to accumulate CPD hours/points/credits. CONCLUSION: Outcomes-based models support registrants' engagement in relevant, meaningful CPD which holds greater potential to positively impact on practice and strengthen patient safety. In funding this study, the UK General Dental Council exemplifies its commitment to reviewing its CPD requirments.

Dental therapists in general dental practice. A literature review and case-study analysis to determine what works, why, how and in what circumstances.

INTRODUCTION: In the United Kingdom, policy and guidance changes regarding the role of dental therapists (DTs) were implemented in recent years with a view to changing dental care to a more preventive-focussed, teamwork approach. However, success in the adoption of this model of working has been varied. AIMS: Adopting a realist approach, our aim was, to examine the use of DTs in general dental practices in Wales, exploring what works, why, how and in what circumstances. MATERIALS AND METHODS: The research comprised two stages. (a) A structured literature search, dual-coding papers for high-level factors describing the conditions or context(s) under which the mechanisms operated to produce outcomes. From this, we derived theories about how skill-mix operates in the general dental service. (b) Six case studies of general dental practices (three with a dental therapist/three without a dental therapist) employing a range of skill-mix models incorporating semi-structured interviews with all team members. We used the case studies/interviews to explore and refine the theories derived from the literature. RESULTS: Eighty-four papers were coded. From this coding, we identified seven theories which reflected factors influencing general dental practices within three broad contexts: the dental practice as a business, as a healthcare provider and as a workplace. We tested these theories in interviews with 38 dental team members across the six care studies. As a result, we amended five of the theories. CONCLUSION: Our analysis provides theory about outcomes that DTs may facilitate and the mechanisms that may assist the work of DTs within different contexts of general dental practice.

The use of isolated natural products as scaffolds for the generation of chemically diverse screening libraries for drug discovery.

A diverse range of strategies leading to natural product derived or inspired screening libraries aims to increase the number of new chemical entities emerging per year. However, the use of isolated natural products as scaffolds for the semi-synthesis of larger biological screening libraries remains rare. This particular method avoids the time-consuming and resource intensive de novo synthetic strategy for scaffold production, and has become more feasible through improvements to synthetic and isolation methodologies. This Highlight examines the increasing popularity of small- to large-sized screening libraries generated directly from isolated natural products. Several of the examples detailed herein show how this strategy can lead to improvements in not only potency but also other important (and often forgotten) drug discovery parameters such as toxicity, selectivity, lipophilicity and bioavailability. However, there are still improvements to be made to this method, particularly in the choice of the natural product scaffold and the derivatising reagents used. Avoidance of known nuisance compounds or structural alert motifs (e.g. PAINS) that interfere with bioactivity screens, and impact downstream drug development will play a significant role in the future success of this methodology. Incorporation of rational design strategies that take into account the physicochemical parameters (e.g. log P, MW, HBA, HBD) of the final semi-synthetic library analogues will also facilitate the discovery and development of leads and drugs. A multi-pronged approach to drug discovery that incorporates the use of isolated natural product scaffolds for library generation will surely be beneficial.

Daldionin, an Unprecedented Binaphthyl Derivative, and Diverse Polyketide Congeners from a Fungal Orchid Endophyte.

Thailand possesses a rich diversity of orchid species that, in turn, live in symbiosis with a wide variety of fungi. Such endophytes have the potential to produce secondary metabolites with bioactivity against orchid and/or human pathogens. The orchid-associated fungal strain Daldinia eschscholtzii was found to produce a diverse range of aromatic polyketides including the new naphthalene derivatives daldionin, nodulones B and C, and daldinones F and G along with eight known compounds. Daldionin possesses an unprecedented oxane-linked binaphthyl ring system. These compounds demonstrate the high diversity of structural variations that are constructed during fungal biosynthesis, and the results include important observations concerning the biosynthesis of binaphthyl derivatives. Daldionin was found to have weak antiproliferative activity against HUVEC and K-562 cell lines. All but one of the isolated compounds showed moderate antimicrobial activity towards at least one of the four tested microbial strains.

The functional diversity of essential genes required for mammalian cardiac development.

Genes required for an organism to develop to maturity (for which no other gene can compensate) are considered essential. The continuing functional annotation of the mouse genome has enabled the identification of many essential genes required for specific developmental processes including cardiac development. Patterns are now emerging regarding the functional nature of genes required at specific points throughout gestation. Essential genes required for development beyond cardiac progenitor cell migration and induction include a small and functionally homogenous group encoding transcription factors, ligands and receptors. Actions of core cardiogenic transcription factors from the Gata, Nkx, Mef, Hand, and Tbx families trigger a marked expansion in the functional diversity of essential genes from midgestation onwards. As the embryo grows in size and complexity, genes required to maintain a functional heartbeat and to provide muscular strength and regulate blood flow are well represented. These essential genes regulate further specialization and polarization of cell types along with proliferative, migratory, adhesive, contractile, and structural processes. The identification of patterns regarding the functional nature of essential genes across numerous developmental systems may aid prediction of further essential genes and those important to development and/or progression of disease.

Case-based discussion supporting learning and practice in optometry.

PURPOSE: To enhance continuing professional development and address the risk that professional isolation poses, the UK General Optical Council introduced a requirement for all optometrists to engage in at least one case-based discussion per 3 year cycle of continuing education. In this paper, we explore participants' impression of the acceptability, effectiveness and long-term impact-on-practice of case-based discussion as a mode of continuing education. METHODS: Case-based discussion participants attended an evening session comprising a lecture and a group discussion. They completed three questionnaires: prior to the session, immediately post-session and 3-4 months post-session. We coded the questionnaires to allow matching. RESULTS: Seventy-five case-based discussion groups were held with 379 participants; 377 completed both pre- and post-questionnaires and 331 (88%) returned a follow-up questionnaire. Case-based discussions were an acceptable method of learning, with many preferring it to distance-learning. Prior to the event, women, employees and part-time workers were more likely to have concerns about participating. In terms of learning, gaps in knowledge were more likely to be revealed in those who work in isolation. The respondents highlighted social aspects, reassurance of practice as well as new learning. Participants significantly improved self-confidence ratings in all key learning areas. At three months post-session, the majority (75%) self-reported that they had implemented their intended changes to practice. CONCLUSIONS: The evaluation showed that participants felt that case-based discussion developed their knowledge, notably for sole practitioners, and influenced later workplace practice. The peer interaction of this mode of continuing education can combat professional isolation.

An extended period of functional appliance therapy: a controlled clinical trial comparing the Twin Block and Dynamax appliances.

The aim of this clinical trial was to compare the hard- and soft-tissue effects of 15 month full-time functional appliance therapy with Twin Block (TB) and Dynamax (Dx) appliances. The effects on both hard and soft tissue were analysed using cephalograms and three-dimensional optical surface laser scans. One hundred and three subjects with a class II division 1 malocclusion, and a minimum overjet of 7mm were available for analysis following stratified randomization according to gender and age. Data was collected at the start of treatment, 15 month therapy, and after 3 month post-treatment observation. Statistical analysis was conducted using analysis of covariance. The results demonstrated both appliances corrected the overjet with significantly increased skeletal dimensional changes with the TB compared with the Dx with forward movement of pogonion of 5.2mm (TB) and 0.7mm (Dx) P = 0.003. In addition, significant changes occurred particularly in the vertical dimension where there was also an increase in total anterior face height in both groups (TB = 6.4mm, Dx = 5.5mm) and significant (P = 0.003) mandibular length changes were also observed (TB = 7.2mm, Dx = 3.8mm). The cephalometric soft-tissue changes were significantly different between the two appliances at soft-tissue pogonion (TB = 9.8mm, Dx = 4.6mm, P = 0.001). Laser scan three-dimansional changes showed significant difference in the lower labial sulcus region where forward movements were observed (TB = 8.2mm, Dx = 6.2mm; P = 0.04). Overall these changes appear to be greater and more stable than those achieved in a previous 9 month study.

An Uncommon Case of Fournier's Gangrene in a Female Patient.

Fournier's gangrene is a rare form of infectious fasciitis in the genital region. It is a rapidly progressing, life-threatening infection that requires immediate diagnosis and treatment. Common risk factors for Fournier's gangrene include diabetes mellitus, obesity, trauma, alcoholism, and cigarette smoking. The infection is more commonly seen in men than women, but we present here a case of Fournier's gangrene in a 74-year-old woman. The incident started as a small lump in the genital region from a fall and progressed into a severe case of necrotizing fasciitis. Emergent surgical debridement and antibiotics were required, as mortality depends greatly on prompt management.

Design and synthesis of screening libraries based on the muurolane natural product scaffold.

The plant-derived natural product 14-hydroxy-6,12-muuroloadien-15-oic acid (1) was identified as a unique scaffold that could be chemically elaborated to generate novel lead- or drug-like screening libraries. Prior to synthesis a virtual library was generated and prioritised based on drug-like physicochemical parameters such as log P, log D(5.5), hydrogen bond donors/acceptors, and molecular weight. The natural product scaffold (1) was isolated from the endemic Australian plant Eremophila mitchellii and then utilised in the parallel solution-phase generation of two series of analogues. The first library consisted of six semi-synthetic amide derivatives, whilst the second contained six carbamate analogues. These libraries have been evaluated for antimalarial activity using a chloroquine-sensitive Plasmodium falciparum line (3D7) and several compounds displayed low to moderate activity with IC(50) values ranging from 14 to 33 µM.

What influences the provision and reception of oral health education? A narrative review of the literature.

OBJECTIVES: Most common diseases of the mouth are preventable through behavioural changes, oral hygiene routines and regular professional care. Research suggests dental professionals may prioritize clinical experience, personal values and preferences over evidence when delivering such interventions. Research also suggests variable rates of patient behaviour change following oral health education (OHE) interactions. This review explores the literature to answer the question: what factors influence the provision and reception of OHE messages and the wider OHE process? METHODS: A structured search of literature was carried out with databases covering a range of academic disciplines (healthcare sciences, social sciences, education). Key words/terms were searched to elicit papers published since 1998. Citation mining (relevant citations within papers) and citation tracking (papers citing relevant papers) were also used. Recurring themes within the papers were identified and coded using NVivo12 and presented in a conceptual model. RESULTS: The studies analysed tended to employ small-scale surveys, larger-scale surveys (some with low response rates), or interview studies of varying sizes. There was also a limited number of review papers. However, several key messages were identified regarding dental professionals' and patients' views on OHE and the factors that influence its provision. Factors that were identified related to the wider social and policy context (macro), community-level factors (meso), the individual practitioner and patient (micro), factors that influenced the nature of OHE interaction and any resulting behaviour change, and how the outcomes of the process influence future OHE interactions for both parties. CONCLUSIONS: The literature highlighted how factors influence the OHE process before, during and after the educational interaction. The resultant conceptual model acknowledges the influence of wider 'upstream' factors alongside interpersonal and individual influences which should be taken into consideration when developing OHE interventions.

'It's their mouth at the end of the day': dental professionals' reactions to oral health education outcomes.

Introduction Research has established varying levels of efficacy of oral health education (OHE) efforts. However, little is known regarding how outcomes impact dental professionals and their OHE practice. This study explores dental professionals' reactions to varying OHE outcomes and their motivations to persist with their efforts.Methods Qualitative, semi-structured interviews were conducted with dental team members working in mainly NHS general dental practices in South Wales, UK. Interviews were conducted face-to-face pre-COVID-19 and then by telephone, transcribed and analysed thematically.Results In total, 30 interviews were conducted (17 dentists, 6 dental therapists and 7 dental nurses). Pleasure was gained from improved patient oral health. Responses to non-adherence included disappointment, frustration and acceptance. Acceptance centred around a shared responsibility for oral care between clinician and patient and reassurance that they had 'done their job'. The unpredictability of patient adherence aided OHE motivation; efforts might eventually inspire patient action or might align with patient readiness to change.Conclusions This study reveals how OHE outcomes impact on dental professionals' perceptions of their role and personal motivations for continued educational efforts with patients. Greater emphasis on both preventative dentistry and self-care, coupled with understanding of the complex factors influencing oral health behaviour, would aid motivation for OHE.

Beating Bipolar: exploratory trial of a novel Internet-based psychoeducational treatment for bipolar disorder.

OBJECTIVES: Psychoeducational approaches are promising interventions for the long-term management of bipolar disorder. In consultation with professionals, patients, and their families we have developed a novel web-based psychoeducational intervention for bipolar disorder called Beating Bipolar. We undertook a preliminary exploratory randomized trial to examine efficacy, feasibility and acceptability. METHODS: This was an exploratory randomized controlled trial of Beating Bipolar (current controlled trials registration number: ISRCTN81375447). The control arm was treatment-as-usual and the a priori primary outcome measure was quality of life [measured by the brief World Health Organization Quality of Life (WHOQOL-BREF) scale]. Secondary outcomes included psychosocial functioning, insight, depressive and manic symptoms and relapse, and use of healthcare resources. Fifty participants were randomized to either the Beating Bipolar intervention plus treatment-as-usual or just treatment-as-usual. The intervention was delivered over a four-month period and outcomes were assessed six months later. RESULTS: There was no significant difference between the intervention and control groups on the primary outcome measure (total WHOQOL-BREF score) but there was a modest improvement within the psychological subsection of the WHOQOL-BREF for the intervention group relative to the control group. There were no significant differences between the groups on any of the secondary outcome measures. CONCLUSIONS: Beating Bipolar is potentially a safe and engaging intervention which can be delivered remotely to large numbers of patients with bipolar disorder at relatively low cost. It may have a modest effect on psychological quality of life. Further work is required to establish the impact of this intervention on insight, knowledge, treatment adherence, self-efficacy and self-management skills.

Mitchellenes A-E, cyclic sesquiterpenes from the Australian plant Eremophila mitchellii.

Chemical investigations of the Australian plant Eremophila mitchellii resulted in the isolation of the novel tetracyclic sesquiterpene lactones mitchellenes A-C (1-3), the new sesquiterpene acids mitchellenes D and E (4 and 5), and the previously reported natural products 14-hydroxy-6,12-muuroloadien-15-oic acid (6), casticin, and centaureidin. The chemical structures of all compounds were determined by extensive 1D/2D NMR and MS data analysis. Mitchellenes A-C are the first tetracyclic sesquiterpene lactones to be reported; a biosynthetic pathway is proposed for these unique secondary metabolites.

Developing an online psychoeducation package for bipolar disorder.

BACKGROUND: Medications are known to be effective for bipolar disorder but treatment non-adherence and psychosocial effects can impact adversely on long-term outcome. Psychoeducation may help address some of these issues. AIMS: This article describes the development of a novel online psychoeducation programme ( www.BeatingBipolar.org ) for patients with bipolar disorder. METHOD: The programme was developed in three stages--a literature review, development of a draft outline of the programme and focus groups with mental health professionals and service users. RESULTS: Data highlighted the importance of presenting a supportive style of programme, realistic stories and positive role models within the programme and providing a variety of information delivery styles. Desired outcomes of the programme were an increased sense of control over bipolar disorder, reduced stigma and improved understanding for family and carers. CONCLUSION: The iterative development process using focus groups with service users and mental health professionals provided important insights into users' needs and preferences as well as identifying valued outcomes. Interactive online psychoeducation materials benefit from a systematic design process which is informed by a range of viewpoints.

Specialized Medical Weight Management Intervention for High-Risk Obesity.

Background: Bundled payments are services rendered at pre-determined costs with the goal of providing high value care. Our institution's Episodes of Care team partnered with its tertiary care obesity center to design a novel medical weight management bundle for employers that would collectively deliver high value obesity services. Objective: As a first step, we sought to evaluate short-term medical weight loss outcomes over 6 months at the obesity center. Methods: We retrospectively analyzed weight loss outcomes on 157 patients with commercial insurance coverage over a period of 6 months. Results: Patients ranged in age from 18-72 years, and 77.7% were female. Patients ranged in weight from 160-443 pounds, with a mean body mass index (BMI) of 42.7 kg/m2 (Class 3a severe obesity; BMI range 28.4-74.5). The prevalence of any obesity-related medical condition was 54.1%; at least a quarter of the patients had either prediabetes or Type 2 diabetes mellitus, approximately a third had hypertension, and over 8% had hyperlipidemia. Mean weight loss from the initial program start date was 6.28% (+/-0.48% standard error of mean [SEM]; 95% confidence interval [CI] 5.34-7.23%). Completers (defined as having at least 6 visits with a medical provider) achieved a higher percentage of weight loss (7.06%) from the initial program start compared to non-completers (4.68%; at least 4-5 visits with a medical provider; P<0.0158). Approximately 50% of patients were able to achieve >7% weight loss, with over 55% of patients achieving at least 3% weight loss or higher irrespective of BMI classification. Conclusions: Specialized medical weight intervention is effective in treating high-risk obesity with complications. This has implications for enhanced long-term cost savings related to employer coverage of such programs for their employees with obesity.

Synthesis and Biological Evaluation of (-) and (+)-Spiroleucettadine and Analogues.

A second-generation enantiospecific synthesis of spiroleucettadine is described. The original reported antibacterial activity was not observed when the experiment was repeated on the synthetic samples; however, significant anti-proliferative activity was uncovered for both enantiomers of spiroleucettadine. Comparison of the optical rotational data and ORD-CD spectra of both enantiomers and the reported spectrum from the natural source have not provided a definitive answer regarding the absolute stereochemistry of naturally occurring spiroleucettadine. Efforts then focussed on alteration at the C-4 and C-5 positions of the slightly more active (-)-spiroleucettadine. Ten analogues were synthesised, with three analogues found to possess similar anti-proliferative profiles to spiroleucettadine against the H522 lung cancer cell line.

Disease trajectories and ACT/RCPCH categories in paediatric palliative care.

The objective of this study was to provide a preliminary description of trajectories of life-limiting conditions (LLCs) using qualitative experiential data. Semi-structured interviews were conducted with families of children with LLCs, selected to encompass all Association for Children's Palliative Care (ACT)/Royal College of Paediatrics and Child Health (RCPCH) categories, using a schedule developed from focus groups of professionals. Thirty out of 76 families agreed to participate. Four of these were unsuitable. In nine out of 26 families, their child had died. In eight out of the 26, two individuals were interviewed. Twenty-four mothers, nine fathers, one sibling and two foster-carers were interviewed in total. The interview schedule was developed from data from four themed focus groups, comprising 25 professionals from 14 backgrounds. Thirty-four milestones in five phases were identified: Diagnosis, Loss of normality, Adjusting to new normality, Palliative phase and Death. Many milestones were common to all categories, suggesting that the ACT/RCPCH system encompasses related conditions. Others occurred in only some, suggesting trajectories in the categories are distinct. Significant themes emerging from qualitative data were: becoming expert in their child, concerns about service provision, information needs and relationships with health professionals. By presenting qualitative descriptive data regarding the lived experience of families of children with LLCs, this study provides preliminary evidence that the ACT/RCPCH categories are suitable tools for research and service development.

A whole-team approach to optimising general dental practice teamwork: development of the Skills Optimisation Self-Evaluation Toolkit (SOSET).

Introduction Studies across the health service reveal benefits of teamwork and barriers to its optimal use. Drawing upon the established Maturity Matrix Dentistry method, the Skills Optimisation Self-Evaluation Toolkit (SOSET) was developed to enable the whole dental team to critically review how they address skill-mix in delivery of patient-centred oral healthcare in their practice. This paper outlines the development of the SOSET and explores its usefulness to general dental practice teams.Methods Research literature and interview data from general dental practice teams were coded for high-level factors (positive and negative) influencing teamwork. We used this coding to identify skill-mix domains, and within each, define criteria. The SOSET process was refined following consultations with dental professionals and piloting.Results Eighty-four papers were coded and 38 dental team members were interviewed across six sites. The SOSET matrix was developed containing nine domains reflecting the use of skill-mix, each containing six development-level criteria. The domains addressed factors such as team beliefs on skill-mix and knowledge of team members' scope of practice, patient demand, the business case, staffing and training, and the practice premises. The process was piloted in 11 practices across South Wales, and feedback was received from 92 staff members. Results showed that the SOSET process was straightforward, that the whole team could contribute to discussion and that it would be used to improve practice. Following piloting, four domains were merged into two new domains, and the number of criteria within all domains was reduced and the wording simplified (seven domains, with four criteria each).Conclusion We used a systematic and rigorous process to develop the SOSET to support dental teams to progress their teamwork practices. Its usefulness was demonstrated in the pilot. The SOSET is now being offered to general dental practices across Wales.

Isolation, structure elucidation and cytotoxic evaluation of endiandrin B from the Australian rainforest plant Endiandra anthropophagorum.

Chemical investigations of the DCM extract from the roots of Endiandra anthropophagorum resulted in the isolation of a new cyclobutane lignan endiandrin B (1), together with the known natural products, endiandrin A (2), and (-)-dihydroguaiaretic acid (3). The structure of 1 was determined by extensive spectroscopic analyses, and confirmed by single crystal X-ray crystallography. Methylation of 1 using diazomethane afforded the previously reported natural product, cinbalansan (4). All compounds were evaluated for their cytotoxicity towards human lung carcinoma cells (A549) using high-content screening. (-)-Dihydroguaiaretic acid (3) was found to be the most potent cytotoxin against the A549 lung carcinoma cell line, with an IC(50) value of 7.49 microM.